Exploiting the endothelial-immune axis to improve radiotherapy efficacy.

The immune system is essential for controlling tumours and plays a crucial role in how normal and cancer tissues respond to radiotherapy. Lining the inner surface of vessels, the endothelium acts as a barrier that normally prevents the passage of cells from the bloodstream into tissues and promotes the recruitment of immune cells during stressful, injured, or infected conditions. Profound changes in endothelial function occur in response to irradiation, determining the tumour response to radiotherapy and participating in the initiation and development of adverse effects. In both normal tissues and tumours, radiation makes endothelial cells more adhesive to circulating cells, stimulates transendothelial migration and promotes immune infiltration, possibly chronic and harmful to normal tissues. Considering the active role of endothelium in immune cell recruitment, targeting endothelial cells becomes an attractive strategy to improve the therapeutic gain of radiotherapy. To this end, it is crucial to better understand how endothelial cells respond to irradiation in vivo and to determine their role in regulating immune cell recruitment. Advanced analytical technologies, such as single-cell RNA sequencing and spatial transcriptomics, now enable to uncover the molecular responses of cells in living organisms and comprehend their interactions within an organ. Here, we present the latest findings regarding the impact of radiation on the vascular endothelium and its implications for normal tissues and tumours. We also explore current research using single-cell analysis to uncover new cell types, molecular pathways, and cell-cell interactions in irradiated animal models and human patients. Additionally, we highlight how endothelial cell-mediated immune recruitment may represent a potential target for modulating the immune response.